The long-term neurological impact of cardio-pulmonary bypass (CPB) surgery can be profound. Recent studies indicate that significant cognitive decline is observed in 42% of CPB-patients when assessed five years after the procedure. This is a substantial biomedical problem because over 500,000 cardiac bypass procedures are performed each year in the United States. The underlying causes of CPB-induced cognitive decline are controversial and not well understood. The overall goal of this application is to characterize mechanisms of CPB-related injury and to evaluate a therapeutic strategy for treating long-term cognitive deficits after CPB. Our preliminary findings indicate that performance on a complex cognitive task is impaired for at least 5-6 months in a rat model of CPB. Studies under Aim #1 will characterize the behavioral impact of CPB in this replicable animal model, and will establish benchmarks for assessing long-term cognitive dysfunction after CPB. Aim #2 will examine three cellular mechanisms proposed to underlie CPB-induced injury: neuroinflammation, suppressed adult neurogenesis, and selective neuronal loss. Preliminary data indicate that sustained, localized neuroinflammation occurs in the hippocampus for at least 6 months after CPB. The preliminary findings also indicate that a substantial decrease in adult neurogenesis occurs in the area of neuroinflammation. These findings, which will be confirmed and extended under Aim #2, spur the hypothesis that sustained neuroinflammation in the hippocampus suppresses adult neurogenesis, which in turn produces long-term cognitive impairment. Aim #3 will test this concept by evaluating the protective effects of anti-inflammatory therapy on the neurogenetic and cognitive consequences of CPB. The benchmarks for behavioral impairment, established under Aim #1, will be used as a measure of cognitive function in these studies. It is hypothesized that blocking the inflammatory response to CPB will attenuate the suppression of neurogenesis and improve cognitive outcome. Together, the proposed studies will: 1) establish a means for assessing long-term cognitive deficits in a rodent recovery model of CPB, 2) characterize fundamental cellular mechanisms that underlie the deleterious effects of CPB, and 3) evaluate a specific therapeutic strategy for blocking and/or reversing cognitive decline associated with CPB. The results will expand our fundamental understanding of the mechanisms underlying CPB-related injury and will assess a rational candidate therapy for limiting cognitive decline after CPB. [unreadable] [unreadable] [unreadable]